The heart generally lacks an endogenous regenerative capacity sufficient for repair after injury. Consequential left ventricular (LV) remodeling after myocardial infarction (MI) leads to LV dilatation, ultimately leading to heart failure (Pfeffer & Braunwald, 1991; Gaudron et al., 1993; Goldstein et al., 1998; Holmes et al., 2005). To reduce this epidemiologic and fiscal burden, it is imperative that strategies be developed to preserve cardiomyocyte survival, subsequently reducing myocardial infarct size, and reducing overall LV remodeling.
Immediately after coronary occlusion, ischemic myocytes downstream from the occlusion become necrotic and/or undergo apoptosis (Cheng et al., 1996; MacLellan & Schneider, 1997; Freude et al., 1998) or autophagy (Nakai et al., 2007; Dorn & Diwan, 2008; Porrello & Delbridge, 2009). Cardiac troponin I is released, which can be measured in plasma and correlates to the size of injury (Bodor et al., 1995; Chapelle, 1999; Braunwald et al., 2002; Nageh et al., 2003; Oyama & Sisson, 2004; Jaffe, 2005). Neutrophils infiltrate the tissue immediately, while leukocytes, predominantly macrophages, arrive shortly thereafter and participate in digestion of necrotic cellular debris. Neutrophils in the ischemic tissue can be toxic to the surrounding myocytes, because they release reactive oxygen species and proteolytic enzymes which further injure the surrounding myocytes (Lefer & Granger, 2000; Frangogiannis et al., 2002; Frangogiannis, 2008; Lambert et al., 2008; Nah & Rhee, 2009). Once damage occurs, a hypocellular scar forms that leads to contractile dysfunction and heart failure (Fishbein et al., 1978; Frangogiannis et al., 2002; Virag & Murry, 2003; Dorn, 2009).
Since the discovery of the Eph (erythropoietin-producing hepatocellular carcinoma) receptor tyrosine kinase (RTKs) in 1987 (Hirai et al., 1987), a great deal of effort has been focused on elucidating Eph receptor tyrosine kinase (RTK) and ephrin ligand signaling in the context of numerous pathologies. A distinguishing characteristic of Eph-ephrin interactions is the ability to generate bidirectional signaling. “Forward” signaling occurs in the direction of the receptor-expressing cell, while “reverse” signaling occurs in the direction of the ligand expressing cell (Bruckner et al., 1997; Mellitzer et al., 1999; Klein, 2001; Kullander & Klein, 2002). Upon ligand binding and receptor activation, endocytic internalization of the complex occurs (Pasquale, 2010), leading to downregulation of the protein. Intracellular cascades downstream of Eph/ephrin signaling are involved in cellular survival, growth, differentiation, and motility (Zhou, 1998; Kullander & Klein, 2002; Arvanitis & Davy, 2008; Pasquale, 2008, 2010). The EphA1 receptor has been linked to angiogenesis through endothelial cell migration. Like the ephrinA1 ligand, EphA1 is induced by TNF-a, VEGF, and leading to cellular adhesion via integrins and vessel destabilization (Pandey et al., 1995; Cheng et al., 2002a; Cheng et al., 2002b; Moon et al., 2007). Similarly, the EphA2 receptor, expressed on endothelial cells, is widely reported as a key player in angiogenesis, particularly in development and cancer (Ogawa et al., 2000; Brantley-Sieders et al., 2004; Brantley-Sieders et al., 2006; Wykosky et al., 2008).
Of the at least five ephrinA ligands, ephrinA1 is unique in that it is currently the only ligand that binds all eight EphA receptors known to be expressed in mice. Aside from its predominant characterization as a pro-angiogenic factor in adult mouse tumors, (Easty et al., 1999; Ogawa et al., 2000; lida et al., 2005), ephrinA1 appears to be involved in inflammation and apoptosis. It was reported in 2006 that Eph receptors are differentially expressed at early and late stages of inflammation (Ivanov & Romanovsky, 2006). For example, at earlier stages of inflammation, EphA2 and EphrinB2 expression is predominantly localized to epithelial and endothelial cells, promoting disruption of the endothelial/epithelial barrier. However, as the inflammatory process progresses, expression of EphA1, EphA3, EphB3, and EphB4 on these cells decreases, allowing infiltrating leukocytes to adhere to endothelial cells by disrupting endothelial/epithelial barriers (Ivanov & Romanovsky, 2006). EphrinA1/EphA receptor expression changes also appear to be involved in regulating pathways involved with apoptosis. In 2006, Munoz and colleagues reported that EphA4 deficient mice exhibited both defective T cell development and increased numbers of apoptotic cells (Munoz et al., 2006).